Exogenous testosterone is vital to gender-affirming therapy for transmasculine individuals. Testosterone may be implicated in breast cancer (BCa) because it can activate androgen and estrogen receptors. To further explore this risk, we performed a systematic review to investigate the impact of exogenous testosterone on BCa risk in transmasculine individuals.

We searched PubMed/MEDLINE and Ovid/Embase for clinical and preclinical studies assessing BCa and testosterone therapy and screened 6125 articles independently. We ascertained level of evidence using a modified tool from Cook et al (Chest. 1992;102:305S-311S) and risk of bias using a modified Joanna Briggs Institute's Critical Appraisal Tool.

Seventy-six studies were included. Epidemiological data suggested that BCa incidence was higher in transmasculine individuals compared with cisgender men but lower compared with cisgender women. Histological studies of transmasculine breast tissue samples also demonstrated a low incidence of precancerous lesions. Interestingly, cases demonstrated that BCa occurred at a younger average age in transmasculine individuals and was predominantly hormone receptor positive. The mechanism for BCa in transmasculine individuals may be related to androgen receptor stimulation or conversion to estradiol. Serum studies reported varied estradiol levels associated with exogenous testosterone. Animal and in vitro studies demonstrated that testosterone was growth inhibitory but may induce proliferation at higher doses or with low estradiol levels.

Plastic surgeons play a critical role in providing gender-affirming care for transmasculine patients. The limited studies available suggest that this patient population has decreased risk for BCa when compared with cisgender women; however, any BCa that does occur may have different clinical presentations and underlying mechanisms compared with cisgender women and men. Overall, the limitations for clinical studies and discrepancies among preclinical studies warrant further investigation.

Antithrombotic and thrombolytic therapies are used to prevent, treat, and remove blood clots in various clinical settings, from emergent to prophylactic. While ubiquitous in their healthcare application, short half-lives, off-target effects, overdosing complications, and patient compliance continue to be major liabilities to the utility of these agents. Biomaterials-enabled strategies have the potential to comprehensively address these limitations by creating technologies that are more precise, durable, and safe in their antithrombotic action. In this review, we discuss the state of the art in anticoagulant and thrombolytic biomaterials, covering the nano to macro length scales. We emphasize current methods of formulation, discuss how material properties affect controlled release kinetics, and summarize modern mechanisms of clot-specific drug targeting. The preclinical efficacy of these technologies in an array of cardiovascular applications, including stroke, pulmonary embolism, myocardial infarction, and blood contacting devices, is summarized and performance contrasted. While significant advances have already been made, ongoing development efforts look to deliver bioresponsive "smart" biomaterials that will open new precision medicine opportunities in cardiology.

Evidence-based standards are fundamental to the practice, funding, and governance of modern medicine. These standards are developed using hierarchies of evidence yet it is often not appreciated that different hierarchies exist and there is a risk that inconsistent standards may be developed depending upon the hierarchy that is used. In this paper, we present four factors, independent of study design, that have led to differences amongst hierarchies. These factors are: establishment of professional jurisdiction, practical concerns, methodological quality, and the importance of different questions within medicine. We demonstrate that each of these factors has led to the upgrading of expert opinion and/or the downgrading of randomized controlled trials and meta-analyses within different hierarchies. Our aim is to raise awareness of factors that have influenced the development of hierarchies. This may make the reader more critical of the processes that are used to develop evidence based standards.

Evidence-based medicine has claimed to be science on a number of occasions, but it is not clear that this status is deserved. Within the philosophy of science, four main theories about the nature of science are historically recognized: inductivism, falsificationism, Kuhnian paradigms, and research programmes. If evidence-based medicine is science, knowledge claims should be derived using a process that corresponds to one of these theories. This paper analyses whether this is the case. In the first section, different theories about the nature of science are introduced. In the second section, the claim that evidence-based medicine is science is reinterpreted as the claim that knowledge claims derived from randomized controlled trails and meta-analyses are science. In the third section, the knowledge claims valued within evidence-based medicine are considered from the perspective of inductivism, falsificationism, Kuhnian paradigms, and research programmes. In the final section, possible counter arguments are considered. It is argued that the knowledge claims valued by evidence-based medicine are not justified using inductivism, falsificationism, Kuhnian paradigms, or research programmes. If these are the main criteria for evaluating if something is science or not, evidence-based medicine does not meet these criteria.

Low Level Laser Therapy (LLLT) is an increasingly studied technique. The authors of a meta-analysis published in 2012 had already confirmed the effectiveness of LLLT for radio-induced mucitis. Our purpose was to check its indication for similar pathologies.

The articles were selected with the PubMed engine. The selected terms were "Low Level Laser Therapy", "oral surgery", "oral infection", "oral inflammation", "oral mucosal lesions", "oral mucosal disease", "stomatitis", "aphtous", "Herpes", "oral lichen planus", and "oral ulceration". The analysis was made on the following criteria: assessment criteria, methodological quality, and bias. We estimated the level of proof according to Sackett's modified score.

Six articles were selected. Two focused on the effectiveness of LLLT for Herpes simplex virus 1 oral symptoms. Two focused on the effectiveness of LLLT for oral lichen planus. One focused on the effectiveness of LLLT for recurrent aphthous stomatitis. The last one focused on the usefulness of LLLT to control stomatitis pain in the hand-foot-and-mouth disease.

All the selected studies were assessed with a Sackett's score of IV. No study presented the required quality standards to recommend the treatment of LLLT for the selected indications.

The objective of this review was to assess the published evidence for an association between glycaemic variability and the development of chronic micro- and macrovascular complications in patients with diabetes mellitus (DM).

A systematic review of English-language literature published from January 1990 through November 2008 was performed. Interventional and observational studies in patients with type 1 or type 2 DM reporting a measure of glycaemic variability and its impact on the development or progression of micro- and macrovascular diabetic complications were assessed.

A total of 18 studies -8 on type 1 DM and 10 on type 2 DM patients-meeting the inclusion criteria were identified. Studies in patients with type 1 DM revealed that glucose variability has little impact on the development of diabetic complications. Only in two of the eight type 1 DM studies did glucose variability have a significant association with microvascular complications, but not with macrovascular complications. Among type 2 DM studies, a significant positive association between glucose variability and the development or progression of diabetic retinopathy, cardiovascular events and mortality was reported in 9 of 10 studies. Only one type 2 DM study reported no association between glucose variability and progression of retinopathy.

Based on this overview of the available evidence, there appears to be a signal suggesting that glucose variability, characterized by extreme glucose excursions, could be a predictor of diabetic complications, independent of HbA1c levels, in patients with type 2 DM. Better daily control of blood glucose excursions, especially in the postprandial period, may reduce the risk of these complications. Future prospective trials evaluating and comparing the effect of the control of glycaemic variability on the development of diabetic micro- and macrovascular complications are needed to further strengthen the evidence base.

Effective screening programs should not merely detect presence of disease, but also lead to long-term benefit. We describe the rationale and design of the first randomized clinical trial to study the long-term effects of routine screening for hearing loss. We also describe the baseline characteristics of the randomized cohort.

We randomized 2305 veterans age 50 years or older to a control arm without screening, or to screening with: physiologic testing (AudioScope), a self-administered questionnaire (Hearing Handicap Inventory for the Elderly-Screening version [HHIE-S]), or both tests. The primary outcome measure will be hearing aid use one year after screening. We will also study a number of secondary outcomes, including appointments made with and visits to an audiologist, cases of aidable hearing loss, hearing aids dispensed, self-rated communication ability, and hearing-related quality of life.

Baseline demographic and health status measures were evenly distributed across the screening arms. The percentage of patients who screened positive for hearing loss was 18.6%, 59.2%, and 63.6% for the AudioScope, HHIE-S, and combined screening arms, respectively.

Long-term results are needed to gain insight into whether the AudioScope is associated with high rates of false negative screening, the HHIE-S is associated with high rates of false positive screening, or a combination of both. Identifying the best screening program will depend on determining which strategy leads to successful hearing aid use.

Dietitians working in hospitals are routinely involved in assessing energy and macronutrient (ie, protein, fat, carbohydrate) requirements of patients. However, complete nutritional therapy requires a comprehensive review of vitamin and mineral requirements. Scientific evidence for vitamin and mineral supplementation is primarily based on healthy, free-living people. This raises clinical challenges for dietitians working with patients whose vitamin and mineral requirements are impacted by various diseases, conditions, and medical treatment. Dietitians are the best-positioned health professionals to lead an evidence-based approach toward recommending vitamin and mineral supplements. The dietitians at the Toronto Rehabilitation Institute were authorized through a medical directive to prescribe multiple vitamins with minerals and to discontinue orders for unnecessary vitamin supplements. This is an ongoing, advanced practice initiative that focuses on the clinical efficacy for and safety of supplementation with multiple vitamins with minerals. It involves assessing the strength of evidence as it emerges in the literature, determining its relevance to specific patient populations in the practice setting and re-evaluating clinical practices for potential applications. When dietitians assume advanced practice initiatives, they are better equipped to deliver high-quality patient care. Simultaneously, state-of-the-art dietetic practice heightens dietitian recognition as a valuable member of the health care team.

Atrial fibrillation (AF) is the most prevalent arrhythmia in hospital emergency departments and is a serious disease associated with a twofold increase in morbidity and a high mortality rate. However, the management of AF in this scenario is variable and frequently inadequate. This is probably a consequence of the diverse clinical aspects and therapeutic options to consider in the management of patients with AF. Therefore, implementation of specific, coordinated management strategies by the different care providers involved is needed to improve the quality of care and optimize the use of human and material resources. This document presents the guidelines recommended by the Spanish Society of Cardiology (SEC) and the Spanish Society of Emergency Medicine (SEMES) for the management of AF in hospital emergency departments. These guidelines are based on published scientific evidence and are applicable to most emergency departments in Spain. Specific management strategies are proposed for the conversion and maintenance of sinus rhythm, heart rate control during AF, prophylaxis for thrombi and emboli, and hospital admission and discharge protocols.

Evidence-based follow-up care of the lung cancer patient is straightforward with periodic histories and physical examinations recommended to detect recurrence. Yearly chest radiographs to detect second primaries "may be reasonable" in small and non-small cell lung cancer patients. The routine use of computed axial tomography (CAT) scans, bone scans, brain imaging, and serum tumor markers is not recommended in lung cancer patients. Many patients receive more extensive and expensive follow-up after treatment, despite the lack of curative options for recurrent lung cancer or evidence that earlier treatment of recurrence leads to better medical outcomes. The reasons for this are not known at present but could involve patient or physician preference, with no disincentives for extra testing. Adherence to breast cancer follow-up clinical practice guidelines at one cancer center reduced cost by one third with no change in health outcomes, but no studies have been performed in lung cancer.

To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma and to determine their respective role relative to other conventional therapies for this condition.

An expert multidisciplinary Panel reviewed pertinent information from the published literature through January 2002. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the Panel. Expert consensus was used if there were insufficient published data. The Panel addressed which patients to treat and when to treat them in the course of their disease. Additionally, specific drug delivery issues, duration of therapy, initiation of treatment and management of treatment of lytic bone disease was reviewed and compared with other forms of therapy for lytic bone lesions. Finally, the Panel discussed patient and physician expectations associated with this therapy for bony metastases, as well as public policy implications related to the use of bisphosphonates. The guidelines underwent external review by selected physicians, by the Health Services Research Committee members, and by the ASCO Board of Directors.

The available evidence involving randomized controlled trials is modest but supports that oral clodronate, intravenous pamidronate, and intravenous zoledronic acid are superior to placebo in reducing skeletal complications. A reduction in vertebral fractures has consistently been seen across all studies. No agent has shown a definitive survival benefit. Intravenous zoledronic acid has recently been shown to be as effective as intravenous pamidronate. Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent cannot be definitively established. However, the panel recommends only intravenous pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it. Additionally, clodronate is not available in the United States. The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 minutes), versus the less expensive drug, pamidronate, with its longer infusion time (2 hours).

Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. However, further research on bisphosphonates is warranted, including the following: (1) when to start and stop therapy, (2) how to integrate their use with other treatments for lytic bone disease, (3) how to evaluate their role in myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine their cost-benefit consequence.

To develop an evidence and consensus based guideline for the management of the child who presents to hospital with diarrhoea (with or without vomiting), a common problem representing 16% of all paediatric medical attenders at an accident and emergency department. Clinical assessment, investigations (biochemistry and stool culture in particular), admission, and treatment are addressed. The guideline aims to aid junior doctors in recognising children who need admission for observation and treatment and those who may safely go home.

A systematic review of the literature was performed. Selected articles were appraised, graded, and synthesised qualitatively. Statements on recommendation were generated.

An anonymous, postal Delphi consensus process was used. A panel of 39 selected medical and nursing staff were asked to grade their agreement with the generated statements. They were sent the papers, appraisals, and literature review. On the second and third rounds they were asked to re-grade their agreement in the light of other panelists' responses. Consensus was predefined as 83% of panelists agreeing with the statement.

Clinical signs useful in assessment of level of dehydration were agreed. Admission to a paediatric facility is advised for children who show signs of dehydration. For those with mild to moderate dehydration, estimated deficit is replaced over four hours with oral rehydration solution (glucose based, 200-250 mOsm/l) given "little and often". A nasogastric tube should be used if fluid is refused and normal feeds started following rehydration. Children at high risk of dehydration should be observed to ensure at least maintenance fluid is tolerated. Management of more severe dehydration is detailed. Antidiarrhoeal medication is not indicated.

The guideline has been successfully implemented and evaluated in a paediatric accident and emergency department.

Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices.

Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus.

For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected.

The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.

To determine the most effective, evidence-based approach to the use of platelet transfusions in patients with cancer.

Outcomes of interest included prevention of morbidity and mortality from hemorrhage, effects on survival, quality of life, toxicity reduction, and cost-effectiveness.

A complete MedLine search was performed of the past 20 years of the medical literature. Keywords included platelet transfusion, alloimmunization, hemorrhage, threshold and thrombocytopenia. The search was broadened by articles from the bibliographies of selected articles.

Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly related to one of the primary outcomes in a randomized design. BENEFITS/HARMS/COST: The possible consequences of different approaches to the use of platelet transfusion were considered in evaluating a preference for one or another technique producing similar outcomes. Cost alone was not a determining factor.

Appendix A summarizes the recommendations concerning the choice of particular platelet preparations, the use of prophylactic platelet transfusions, indications for transfusion in selected clinical situations, and the diagnosis, prevention, and management of refractoriness to platelet transfusion.

Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board reviewed this document.

American Society of Clinical Oncology

To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials.

The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated.

The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity.

An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed.

Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus.

The recommendations, suggestions, and expert opinions of the Panel are described in this article.

Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

The ascendancy of EBM has been accompanied by a greater awareness of its shortcomings. It is increasingly evident from the cost, length, and difficulty of performing RCTs that studies cannot be launched to address every question in medicine. Good evidence is often lacking in medicine. Epistomologists question the very notions of evidence and the suitability of current study designs and measurement tools to research the salient issues of concern to patients and others concerned with quality. Lack of evidence of effectiveness does not prove ineffectiveness, yet, in reaction to EBM, insurance companies and government often make this inference to justify decisions to withhold coverage or research support. The unbridled enthusiasm for the evidence-based practice guideline of the early 1990s has been tempered by a more mature understanding of its limitations. Not many practice guidelines are developed well, and the implementation of flawed guidelines can cause harm. The seven-step process outlined earlier is slow, laborious, and expensive (sometimes costing hundreds of thousands of dollars). Moreover, there is little evidence that either the rigor of the methods or the guidelines themselves have a meaningful effect on practice behavior or patient outcomes. To the most cynical observers, the only consistent beneficiaries of guidelines are payers, who use guidelines with considerable success in reducing costs, lengths of stay, and utilization rates. Even ardent advocates of guidelines acknowledge the evidence that disseminating reviews and recommendations, by itself, fails to motivate clinicians to increase delivery of effective interventions and to abandon ineffective ones. This absence of response has stimulated a closer look at the barriers to behavior change and the design of thoughtful implementation strategies that begin with, but reach beyond, simple guidelines. Tools such as reminder systems, standing orders, academic detailing, peer review and audit, feedback, and health system changes recognize that knowing what to do is only one piece of an increasingly complex puzzle. The competitive marketplace of managed health care has added new economic influences on clinician behavior but is also fueling private-sector interest in good research. Patients, clinicians, and policy makers will continue to seek better data concerning what works in medicine and what does not.

To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition.

An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors.

Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials.

Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.

To illustrate the complexities of the evidence-based approach in clinical oncology practice and the implications for guidelines and evaluation of processes of care.

A case report is presented in which a limited systematic review of the literature was used to address a specific clinical problem in an individual patient. Experts' opinions were also sought.

A reasonable clinical decision was made by a participating patient based on indirect evidence of benefit that would be insufficient to support the same decision as a health policy in some jurisdictions.

The practice of evidence-based oncology requires clinical judgment about the validity and applicability of research evidence. The factors that influence an evidence-based decision in the clinical context differ from those in the broader policy context, which could lead to legitimate differences in recommendations based on the same information. Used properly, the individual case report can be a powerful tool to illustrate complex clinical decision phenomena.

Data describing the use of ventilation as a bridge to lung transplantation are scant. However, data from the International Registry suggest that patients who are ventilated at the time of transplantation are at increased risk. The decision to offer invasive ventilatory support to a lung transplant candidate with acute respiratory failure should be individualized and based on variables that include likelihood of expeditious transplantation, and the presence of a reversible superimposed process. A trial of NPPV is justified in patients who present in acute respiratory failure, but is more likely to be successful in patients with hypercapnia and chronic airway obstruction. Lung transplant candidates with chronic respiratory insufficiency secondary to obstructive airway disease are at increased risk of acute respiratory failure, and a trial of NPPV might be considered on an individual basis after maximization of conventional medical therapy. More research in this area is necessary to further define the roles of both invasive and noninvasive ventilation as bridge therapy to lung transplantation.

Tamoxifen, an oestrogen antagonist routinely used in the treatment of breast cancer, has been used in clinical trials for patients with melanoma since the late 1970s. Following initial promise as a single agent for the treatment of metastatic melanoma, tamoxifen was first combined with chemotherapy in this setting in 1984. Since then, numerous phase II studies have combined tamoxifen with different chemotherapeutic agents, with some suggesting that tamoxifen significantly improves the efficacy of cisplatin-containing regimens. Overall response rates range from 8 to 60%. Several randomised trials also have been completed, with response rates of 12-30%. One such study showed statistically significant improvements in response rate and survival when tamoxifen was added to dacarbazine; however, other studies have not observed these benefits with the addition of tamoxifen to cisplatin-containing regimens. At present, the author's opinion is that the strength of evidence does not support the use of tamoxifen in combination with cisplatin-containing chemotherapy for the treatment of metastatic melanoma. Controversy remains as to whether the strength of evidence from the randomised trials outweighs the combined evidence from numerous nonrandomised trials. Resolution of this controversy may depend on the results of the North Central Cancer Therapy Group and/or a common agreement as to relative strength of evidence from clinical trials of different designs.

In current clinical practice, it is important to be able to evaluate the evidence supporting each of our actions. Physicians can no longer rely on tradition or habit; however, with the increasing number of journals available, it is impossible for the practicing clinician to keep abreast of all the relevant literature. One valuable method of gathering and summarizing the latest information and opinions is the use of round tables and consensus conferences. Published reports of round table and consensus conference findings can be invaluable in guiding the clinician.

This study sought to determine whether the time to first recurrence of syncope after a positive isoproteremol-tilt table test result accurately predicts the eventual frequency of syncope.

Both patient care and future clinical trials involving patients with neuromediated syncope will require a simple measure that reflects the frequency of syncope. The time from tilt table testing to the first recurrence of syncope might be such a measure.

A cohort of 46 patients with syncope, in a university outpatient clinic, who had at least one syncopal spell after a positive isoproterenol-tilt table test result were followed up for up to 6.5 years (mean [+/-SD] 48 +/- 14 months). The time from tilt table testing to the first recurrence of syncope was correlated.

A total of 40 of 46 patients had more than one recurrent spell, with a median of eight recurrent spells. The time to the first syncopal spell predicted the frequency of spells with r = -0.79 (p < 0.001), whereas the time to the second spell predicted the frequency with r = -0.92 (p < 0.001). Patients who fainted within 1 month of tilt testing had a geometric mean frequency of 1.35 spells/month (95% confidence limits 0.49, 3.74) compared with patients who fainted 1 to 24 months after testing (0.12 spells/months; 95% confidence limits 0.07 to 0.18, p < 0.001). Finally, the frequency of syncopal spells bore no relation to the duration of follow-up.

The time to the first recurrent spell predicts the frequency of syncopal spells after a positive tilt table test result, and the instantaneous risk of syncope is constant.

Experimental designs in clinical investigation are discussed in this article. Guideline examples have been used in the area of Cardiology using always the same one only one whenever possible. We have looked for a different perspective from what is generally used in the discussion of the general characteristics of experimental designs, and more specifically of clinical trials and we deal with the aspects of clinical trials which are usually ignored due to their marginal character. We also discuss those characteristics which differentiate clinical trials in respect to other designs and types of questions which are answered by clinical trials. And we finally discuss various aspects such as randomization and its various types (simple, block, stratified, pre-randomized) and variable types of evaluating the answers, masking and the problems in its maintenance, with certain kinds of designs, sample size, etc. There is a brief mention of two particular cases: factorial and cross over designs are both discussed, mentioning their strong and weak points. Likewise, we discuss community trials as another experimental design and examples are provided. Finally, we discuss aspects of criteria: such as, When to stop the trials? or Who are the results applicable to?, and we suggest points to take into consideration when these decisions are made.

To report a cost-effective and scientifically based algorithm for the clinical assessment and treatment of patients with transient ischemic attack (TIA) or minor ischemic stroke.

We comprehensively reviewed the literature on the epidemiologic features, assessment approaches, and treatment recommendations for ischemic cerebrovascular disease and developed an algorithm by using the available clinical and research data to support all decision-making steps.

For patients with TIA or minor ischemic stroke, the appropriate setting for investigation (inpatient or outpatient), suggested diagnostic tests, use of anticoagulants and antiplatelet agents, and indications for surgical treatment are reviewed.

Although stroke is a common cause of death and lost productivity in the United States, the clinical assessment of patients with TIA or minor ischemic stroke has lacked consistency. The simplified algorithm clarifies patients who may be candidates for hospitalization and possible anticoagulation therapy. Initial diagnostic studies should include computed tomography of the head without use of a contrast agent, which quickly distinguishes nonhemorrhagic from hemorrhagic cerebrovascular disease. Evolving noninvasive studies of the cerebral vasculature are providing increasingly sensitive means of detecting stenoses, yet cerebral angiography remains the "gold standard." Treatment options depend on the pathophysiologic findings on diagnostic evaluation.

The assessment of patients with ischemic cerebrovascular disease is complex. The simplified algorithmic approach reported herein necessitates entry of appropriate patients into the algorithm. Because of clinical heterogeneity, an algorithm may apply to a wide spectrum of patients but will not cover every situation; hence, evaluation must be guided by a patient's unique history and findings on examination and by the physician's clinical experience.